FDA Publishes Revised Process-Validation Guidance

FDA published its long-awaited guidance titled Process Validation: General Principles and Practices this week. The document, which revises and replaces the 1987 guidance titled Guideline on General Principles of Process Validation, explains the components of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients. The guidance emphasizes the importance of risk-based decision making and recommends that the degree of control over attributes be commensurate with their risk to the process or output.

The new guidance categorizes process-validation activities into three stages.
During Stage 1, process design, a company defines the commercial process based on what it has learned throughout development and scale-up activities. The document recommends that companies use design-of-experiment studies and risk-analysis tools to understand process variables. In Stage 1, a company should develop strategies to control processes by reducing the variation of inputs, adjusting equipment to compensate for input variation, or both tactics. Process design must be based in science, and decisions about design should be documented, according to the guidance.

During Stage 2, process qualification, a company should evaluate its process design. This evaluation should include an examination of the facility and the qualification of equipment and utilities, according to the guidance. In addition, personnel should carry out process-performance qualification (PPQ) to confirm the process design and demonstrate that the commercial manufacturing process performs as expected. “The approach to PPQ should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control,” according to the document. PPQ requires a written protocol that describes items, such as manufacturing conditions, data to be collected, tests to be performed, and the sampling plan. The ultimate decision to begin commercial distribution should be supported by data from commercial-scale batches, according to the guidance.

Stage 3, continued process verification, provides ongoing assurance during routine production that the process remains in a state of control. This goal requires a system for detecting deviations from the process. “Adherence to the CGMP [current good manufacturing practice] requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability” and help personnel determine whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control, according to the guidance.

During this stage, a company should establish an ongoing program to collect and analyze product and process data that relate to product quality. Trained personnel should statistically trend and review the data, and the information collected should verify that the quality attributes are appropriately controlled throughout the process, according to the guidance.